Abstract 4970: Mutational and functional analysis reveals ADAMTS18 metalloproteinase as a novel driver in melanoma

Abstract

Abstract An important feature of cellular signaling and migration involves the proteolytic cleavage of extracellular matrix and/or pro-ligands involved in signal transduction. Proteins called proteases are responsible for this action and include the matrix-metalloproteinase family and the A Disintegrin and Metalloproteinases family to name a few. The A Disintegrin and Metalloproteinases with Thrombospondin domains (ADAMTS) have been suggested to function as tumor suppressors as several have been found to be epigenetically silenced in various cancers. Thus further analysis is warranted in determining if ADAMTS genes/proteins play a role in melanoma genesis. In the present study we performed a mutational analysis of 19 ADAMTS gene family members in human melanoma and identified a large fraction of melanomas to harbor somatic mutations. To evaluate the functional consequences of the most commonly mutated gene, ADAMTS18, six of its mutations were biologically examined. ADAMTS18 mutations had little effect on melanoma cell growth under standard conditions, but reduced cell dependence on growth factors. ADAMTS18 mutations also reduced adhesion to Laminin-I and increased migration in vitro and metastasis in vivo. Melanoma cells expressing mutant ADAMTS18 had reduced cell migration after shRNA-mediated knockdown of ADAMTS18, suggesting that ADAMTS18 mutations are growth-, migration- and metastasis- promoting in melanoma. These results demonstrate that the ADAMTS18 is a major target for mutational activation in melanoma and may be a useful diagnostic and/or therapeutic target. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4970. doi:10.1158/1538-7445.AM2011-4970